My ultimate career goal is to become an independent investigator at an academic institution and perform cutting edge research in the field of cancer biology. As a graduate student, I was highly productive, publishing 5 first author papers (10 total papers). I then traveled from Cincinnati to Portland to join Dr. Liskay's laboratory. I have been a postdoctoral fellow for just over 4 years and I have published two first author papers in Oncogene and Carcinogenesis. To continue toward my goal of becoming an independent investigator, I have proposed two years of mentored research in cancer biology with new training in high- throughput bioinformatics, mathematical modeling and xenografts. This K99 award will allow me to not only continue my current work, but also broaden the base of knowledge, which will help me to successfully start a lab of my own that can address important questions in the field of cancer biology by combining bioinformatics, mathematical modeling and mouse models of cancer. During my training, I will be applying for independent tenure-track positions at academic research institutes throughout the United States. An integral part of my training involves complex experimentation with mice~ therefore, as part of my training I plan to attend the Workshop on Surgical Techniques in the Laboratory Mouse offered at the Jackson Laboratory. I also hope to attend the Workshop on Techniques in Modeling Human Cancer in Mice at the Jackson Laboratories. To further my training, I will take a six-week writing course offered by the Vollum Institute at OHSU. This course is designed to enhance my writing of both manuscripts and grant proposals. During my mentored training, I will gain valuable research skills and career training from three well established researchers with a broad spectrum of biological backgrounds. I also plan to take several courses on Bioinformatics offered at OHSU. Dr. Liskay specializes in colon cancer and mutation~ Dr. Shibata specializes in colon cancer, mathematical modeling of stem cell biology and pathology~ and Dr. Spellman specializes in high-throughput bioinformatic analyses. The breadth of training will help make me adaptable in the future as the field of biology advances and changes. OHSU has outstanding facilities and resources available to support my research as well as my career development throughout the K99/R00 award. Animal facilities are located in an adjacent building in the Department of Comparative Medicine, which has full accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), and letters of insurance are on file with the NIH in the Office of Animal Laboratory Welfare (OLAW). OHSU also offers a variety of core facilities including flow cytometry/FACS, DNA sequencing, Histopathology and Biostatistics. In particular, I will be using the Gene Profiling Shared Resource (GPSR) and the Massively Parallel Sequencing Shared Resource (MPSSR). OHSU is a top-20 research institute with a wide range of resources to both develop my research plan and pursue my goal of being an independent investigator. The Department of Molecular and Medical Genetics at OHSU is committed to providing exceptional resources and training opportunities to me as I transitions to an independent investigator. My postdoctoral training at Oregon Health and Science University is focused on intestinal cancer. I have concentrated on using a novel mouse model of cancer, the Pms2cre mouse. This mouse allows for the isolated, genetic manipulation of genes in a background of normal cells, thus mimicking sporadic cancer. The results of my work were published in Oncogene where I found a phenotypic difference between stepwise (model of inherited cancer) and simultaneous (model of sporadic cancer) Apc loss. This work was important because it suggested that inherited cancer forms via a different mechanism compared to sporadic cancer. I also recently published my work in Carcinogenesis, where I found that intestinal adenoma formation requires a critical sized field of Apc-deficient crypts for tumor initiation and importantly that NSAIDs work as a chemopreventive of adenoma formation by blocking the formation of this field. This K99 proposal continues my work with the Pms2cre mouse model and Apc loss in the intestine, while also addressing issues with chemoprevention and using different mouse models, organoid culture and xenografts to further understand the transition from normal to transformed. The long term objectives of this proposal are to understand the transition of an intestinal stem cell from normal to tumor following mutation in key tumor suppressors and oncogenes. This objective will be achieved by using several different mouse models, intestinal organoids and xenografts. Specifically, I will study the genetic pathways of Apc-deficient occult progression, which results in efficient tumor initiation (Aim 1). While these studies are happening, I will study the effects of Apc mutation and sulindac on intestinal stem cell neutral drift (Aim 2). In parallel, I will study the dynamics of Apc-deficient intestinal cells in cultured miniguts and human cancer cell line derived xenografts (Aim 3). Intestinal cancer is the third leading cause of cancer in the United States and this research will help us understand the fundamental causes of its initiation, progression and prevention.